Assessment of an abridged melarsoprol treatment schedule against late stage Trypanosoma brucei rhodesiense sleeping sickness, multinational phase II study (proof of concept)

2012 ◽  
Author(s):  
Johannes Blum
Keyword(s):  
Trypanosoma Brucei ◽  
Phase Ii ◽  
Late Stage ◽  
Phase Ii Study ◽  
Sleeping Sickness ◽  
Treatment Schedule ◽  
Proof Of Concept ◽  
Trypanosoma Brucei Rhodesiense

scholarly journals Efficacy of the Novel Diamidine Compound 2,5-Bis(4-Amidinophenyl)- Furan-Bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense Infection in Vervet Monkeys after Oral Administration

2008 ◽  
Vol 53 (3) ◽  
pp. 953-957 ◽  
Author(s):  
R. E. Mdachi ◽  
J. K. Thuita ◽  
J. M. Kagira ◽  
J. M. Ngotho ◽  
G. A. Murilla ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Early Stage ◽  
Vervet Monkey ◽  
Sleeping Sickness ◽  
Vervet Monkeys ◽  
Trypanosoma Brucei Rhodesiense ◽  
Dose Rates ◽  
Group 4 ◽  
Group 5

ABSTRACT Owing to the lack of oral drugs for human African trypanosomiasis, patients have to be hospitalized for 10 to 30 days to facilitate treatment with parenterally administered medicines. The efficacy of a novel orally administered prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methlylamidoxime (pafuramidine, DB289), was tested in the vervet monkey (Chlorocebus [Cercopithecus] aethiops) model of sleeping sickness. Five groups of three animals each were infected intravenously with 104 Trypanosoma brucei rhodesiense KETRI 2537 cells. On the seventh day postinfection (p.i.) in an early-stage infection, animals in groups 1, 2, and 3 were treated orally with pafuramidine at dose rates of 1, 3, or 10 mg/kg of body weight, respectively, for five consecutive days. The animals in groups 4 and 5 were treated with 10 mg/kg for 10 consecutive days starting on the 14th day p.i. (group 4) or on the 28th day p.i. (group 5), when these animals were in the late stage of the disease. In the groups treated in the early stage, 10 mg/kg of pafuramidine completely cured all three monkeys, whereas lower doses of 3 mg/kg and 1 mg/kg cured only one of three and zero of three monkeys, respectively. Treatment of late-stage infections resulted in cure rates of one of three (group 4) and zero of three (group 5) monkeys. These studies demonstrated that pafuramidine was orally active in monkeys with early-stage T. brucei rhodesiense infections at dose rates above 3 mg/kg for 5 days. It was also evident that the drug attained only minimal efficacy against late-stage infections, indicating the limited ability of the molecule to cross the blood-brain barrier. This study has shown that oral diamidines have potential for the treatment of early-stage sleeping sickness.

scholarly journals Interleukin (IL)-6 and IL-10 Are Up Regulated in Late Stage Trypanosoma brucei rhodesiense Sleeping Sickness

2015 ◽  
Vol 9 (6) ◽  
pp. e0003835 ◽  
Author(s):  
Charles D. Kato ◽  
Vincent P. Alibu ◽  
Ann Nanteza ◽  
Claire M. Mugasa ◽  
Enock Matovu
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Sleeping Sickness ◽  
Trypanosoma Brucei Rhodesiense

Short Course Radiotherapy Concomitant with Temozolomide in GBM Patients: A Phase II Study

2017 ◽  
Vol 103 (5) ◽  
pp. 457-463 ◽  
Author(s):  
Laura Fariselli ◽  
Lucia Cuppini ◽  
Paola Gaviani ◽  
Marcello Marchetti ◽  
Valentina Pinzi ◽  
...  
Keyword(s):  
Total Dose ◽  
Phase Ii ◽  
Local Control ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Treatment Schedule ◽  
Open Label ◽  
Macdonald Criteria ◽  
Secondary Endpoints ◽  
Group B

Purpose Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM. Methods This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day. Results The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS. Conclusions To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation.

scholarly journals New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients

2013 ◽  
Vol 2 (1) ◽  
Author(s):  
Natalia Tiberti ◽  
Enock Matovu ◽  
Alexandre Hainard ◽  
John Charles Enyaru ◽  
Veerle Lejon ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Sleeping Sickness ◽  
Trypanosoma Brucei Rhodesiense ◽  
New Biomarkers

scholarly journals A New NonpolarN-Hydroxy Imidazoline Lead Compound with Improved Activity in a Murine Model of Late-Stage Trypanosoma brucei brucei Infection Is Not Cross-Resistant with Diamidines

2014 ◽  
Vol 59 (2) ◽  
pp. 890-904 ◽  
Author(s):  
Carlos H. Ríos Martínez ◽  
Florence Miller ◽  
Kayathiri Ganeshamoorthy ◽  
Fabienne Glacial ◽  
Marcel Kaiser ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Late Stage ◽  
Parent Compound ◽  
Central Nervous System Infection ◽  
Sleeping Sickness ◽  
Intrinsic Activity ◽  
Cross Resistance ◽  
Content Type

ABSTRACTTreatment of late-stage sleeping sickness requires drugs that can cross the blood-brain barrier (BBB) to reach the parasites located in the brain. We report here the synthesis and evaluation of four newN-hydroxy and 12 newN-alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluatedin vitroagainstTrypanosoma brucei rhodesienseandin vivoin murine models of first- and second-stage sleeping sickness. Resistance profile, physicochemical parameters,in vitroBBB permeability, and microsomal stability also were determined. TheN-hydroxy imidazoline analogues were the most effectivein vivo, with 4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was foundin vitro, suggesting thatN-hydroxy imidazolines are metabolically stable and have intrinsic activity againstT. brucei. In contrast to its unsubstituted parent compound, the uptake of 14d inT. bruceiwas independent of known drug transporters (i.e.,T. bruceiAT1/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, theN-hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents.

Phase II study for the suboptimally debulked advanced ovarian cancer: Intravenous platinum followed by interval debulking surgery and intravenous paclitaxel + intraperitoneal cisplatin (KCOG9812 study)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5576-5576
Author(s):  
H. Tsubamoto ◽  
K. Ito ◽  
Y. Itani ◽  
K. Ito ◽  
T. Iijima ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Stage Iiib ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Debulking Surgery ◽  
Interval Debulking Surgery ◽  
Grade 3

5576 Background: Intraperitoneral administration (IP) of cisplatin is recommended by National Cancer Institute for the patients with optimally debulked epitherial ovarian cancer (EOC). However, the advantage is not determined for the suboptimally debulked EOC after the initial surgery. We conducted a phase II study of cisplatin IP after the interval debulking surgery (IDS) following 3 cycles of intravenous platinum. Methods: The initial planned sample size was 30. Eligible patients had previously untreated, histologically confirmed EOC or primary peritoneal carcinoma (PPC) of FIGO stage IIIB-IV with suboptimal (> 1 cm) residual disease. Carboplatin AUC 4 iv d1 and cisplatin 50 mg/sqm iv d3 q21d for 3 cycles. After IDS, paclitaxel 175 mg/sqm iv d1 (or paclitaxel 60 mg/sqm iv d1,d8,d15) and cisplatin 75mg/m2 IP q21d for 4 cycles. Primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and toxicity. Results: 33 patients were enrolled since 1998 till 2005. The median age was 55 (range 19–77). ECOG PS 0/1/2 = 33%/36%/31%; stage IIIB/IIIC/IV = 6%/64%/30%; 91% serous papillary histology. Optimal interval debulking surgery was possible in 85%: none (61%), < 1 cm (24%). Grade 3 or 4 (CTCAE ver.3) non-hematologic toxicity was seen in one patient of neurotoxicity. Grade 3 or 4 hematologic toxicities include: neutropenia (37%), infection (4%), thrombocytopenia (11%). 55% were completed the treatment schedule. The reasons for discontinuing were drug resistance (12%), subileus (4%), elevation of serum creatinine (12%), G3 neurotoxicity (4%), IP catheter block (12%) and infection (4%). Primary recurrent sites of total 20 patients before the second line chemotherapy or surgery were peritoneal cavity (30%), distant metastasis (45%), retroperitoneal lymph nodes (15%), and elevation of serum CA125 (10%). Median PFS was 24 months; median overall survival was 48 months; median follow-up was 36 months (range 15–100). Conclusions: This treatment including cisplatin IP after IDS for the patients with the initially suboptimally debulked EOC was feasible, and showed good prognosis with the small number of the intraperitoneal recurrence. [Table: see text]

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